Disubstituxed derivatives of g-amino



Patented Sept. 1, 1 953 DIS UBSTITUTED DERIVATIVES OF G-AMINO- 1,2,3,4 TETRAHYDRO 2,4 PYRIMIDINE- DION ES Viktor Papesch, Morton Grove, and Elmer F. Schroeder, Chicago, 111., assignors to G. D. Scarle & 00., Chicago, 111., a corporation of Illinois No Drawing. Application December 29, 1951, Serial No. 264,248

13 Claims. (01. 260-25611) The present invention relates to a new class of heterocyclic compounds and particularly to disubstituted derivatives of 6-amino-1,2,3,4-tetrahydro-2,l-pyrimidinediones of the following wherein one of the R radicals represents a lower unsaturated aliphatic hydrocarbon radical and the other radical is a member of the class consisting of lower alkyl, hydroxyalkyl, aralkyl, and aryl radicals.

In the foregoing structural formula, one of the R radicals represents an unsaturated aliphatic hydrocarbon radical such as vinyl, propenyl, butenyl, pentenyl, hexenyl, pentadienyl, propargyl, butynyl, and pentynyl, as well as alkyl substituted derivatives thereof such as methylallyl, ethylallyl, methylcrotyl, methylpentyl, methylpropargyl and the like. The other R radical can be an alkyl radical such as methyl, ethyl, straight or branched chain propyl, butyl, amyl, and hexyl; aralkyl radicals such as benzyl, phenethyl, phenylpropyl; and aryl radicals such as phenyl, tolyl, and the like.

In our U. S. Patent No. 2,567,651, we described a series of 1,3-dialkyl-6-amino-1,2,3A-tetrahydro-2,4-pyrimidinediones which have shown a high degree of therapeutic and especially of diuretic activity. The diuretic activity of one of these compounds, l-propyl-S-ethyl-S-amino- 1,2,3, l-tetrahydro-2,4-pyrimidinedione, has been described by A. A. Kattus and E. V. Newman in J. Clin. Inv. 29:82'7; 1950, who found that this compound on oral administration produced a striking diuresis comparable to that obtained with a parenteral mercurial, Thiomerin. It has now been found that compounds of comparable and even higher activity are obtained when one of the alkyl radicals is replaced by an alkenyl radical. In addition, it has been possible to reduce the incidence of toxic reactions by such a change in certain instances.

It is the object of this invention to provide novel chemical substances of the type described above and the methods for producing the same. Thus, the special purpose of this invention is to provide therapeutically active compounds. Our new compounds show valuable therapeutic properties in improving not only renal functions but also those of the cardiovascular system. Further, these compounds are valuable as active ingredients in parasiticidal compositions of matter.

The compounds which comprise this invention are also useful intermediates in chemical syntheses. For instance, the addition of mercuric compounds such as mercuric acetate to the alkenyl group yields valuable mercurials which will be the subject of a separate application.

Some of these disubstituted 6-amino-1,2,3,4- tetrahydro-2,4-pyrimidinediones may be nitrosated to form the corresponding 5-nitroso derivatives. Such nitroso derivatives can be reduced with an agent such as ammonium sulfide to the corresponding 5,6 diamin0- 1,2,3,4- tetrahydro- 2, i-pyrimidinediones. The latter can be heated with formic acid to prepare the 5-formylamino derivatives which are cyclized by heating for a short time with alkali to form the l-alkyl-S-alkenylxanthines and 1-a1keny1-3alkylxanthines which are also the subject of a separate application.

In one of the preferred methods for obtaining the compounds of this invention, an N-alkenyl- N'-alkylurea is treated with acetic anhydride and cyanoacetic acid at a temperature of 50 to 100 0., whereby a mixture of the N-cyanoacetyl- N-alkyl-N-a1kenylurea and the N-cyanoacetyl- N-alkenyl-N-alkylurea is formed. This mixture of ureas is then cyclized by treatment with alkali at temperatures of 40 to 100 C. for a few minutes. From such a mixture the isomers can be separated by fractional crystallization. However, since both isomers usually show a comparable degree of chemotherapeutic activity, use of the mixture of both isomers may be advisable. We have found that in the mixture produced by this process the predominating isomer will be the one in which the radical in the 1-position is larger than the one in the 3-position.

In order to prepare the pure l-alkenyl-S-alkyl isomer, it is preferable to treat the alkenylurea with cyanoacetic acid, cyclize the resulting N-alkenylN-cyanoacetylurea to form the l-alkenyl- 6-amino-l,2,3,4-tetrahydro -2,4- pyrimidinedione and alkylate the latter in the 3-position with an alkylating agent such as an alkyl halide or alkyl sulfate. In another method of preparing the same type of isomer, an ester of cyanoacetic acid, such as ethyl cyanoacetate is reacted with an alkylamine to prepare the N-alkyl cyanoacetamide. The latter is then reacted with an alkenyl isocyanate to form the N-cyanoacetyl-N-alkyl- N-alkenylurea, which is then cycl-ized with alkali to form the pure 1-a1kenyl-3-alkyl-6-amlno- 1,2,3,4-tetrahydro-2,4-pyrimidinedione.

The pure 1-alkyl-3-alkenyl isomer is suitably prepared by reacting the 1-alkyl-6-amino-1,2,3,4- tetrahydro-2,4-pyrimidinedione with an alkenylating agent such as an alkenyl halide. This isomer can also be prepared by reacting an N-alkenyl cyanoacetamide with an alkyl isocyanate and ring closure of the resulting N-cyanoacetyl- N-alkenyl-N'-alkylurea. The aralkyl and aryl derivatives are made by methods analogous to those mentioned for the alkyl derivatives, with the exception that difliculties may be expected in the treatment of the l-alkenyl-6-amino-1,2,3,4- tetrahydro-2,4-pyrimidinediones with certain aryl halides. In these cases, the alternate procedures indicated above are to be preferred.

The following examples illustrate in detail certain of the compounds which comprise this invention and methods for producing them. The invention is not to be construed as limited thereby in spirit and in scope. It will be apparent to chemists skilled in the art that many modifications in materials and methods can be made without departing from our invention. In this application the temperatures are given uncorrected in degrees centigrade (C.), the quantities of materials in parts by weight, and pressure during vacuum distillation in millimeters (mm.) of mercury.

The present application is a continuation-inpart of our copending appliaction, Serial No. 198,028, filed November 28, 1950, now abandoned, and Serial No. 254,196, filed October 31, 1951.

Example 1 85 parts of mono-allylurea are dissolved in 105 parts of acetic anhydride, and 85 parts of cyanoacetic acid are added gradually and the mixture is maintained at 65 C. for 2.5 hours. The mixture is distilled at 20 millimeters until a syrup remains. 50 parts of water are added to this syrup and distillation is resumed. The resulting syrup is dissolved in 96% ethanol at 60 C., stirred with charcoal and filtered. One to one and one half volumes of ether are added to the filtrate at 40 C. Upon cooling the N- cyanoacetyl-N-allylurea precipitates. It is collected on a filter and washed with ether. The white crystals melt at about 142-143 C. The N-cyanoacetyl-N'-allylurea is dissolved by warming with 10% sodium hydroxide. Suiiicient 70% sodium hydroxide is added to raise the pH to 10. The solution is maintained at 60 C. for five minutes. After cooling the crystals are collected on a filter and recrystallized from water. 1 allyl 6 amino 1,2,3,4 tetrahydro 2,4 pyrimidinedione is obtained in the form of white crystals melting at 270-272" C. The 3-allylxanthine prepared from this pyrimidinedione melts at about 301-303 C.

Example 2 100 parts of 1-allyl-6-amino-l,2,3,4-tetrahydro-2,4-pyrimidinedione are dissolved in a solution of 26 parts of sodium hydroxide in 250 parts of water. In the course of one-half hour, 108 parts of dimethyl sulfate are added dropwise to this solution at a temperature of 50-55 C. Heating and stirring are continued for an additional half hour, the alkaline reaction being maintained by occasional addition of small portions of sodium hydroxide, about 150 parts in all being required. On cooling, a crystalline 4 product slowly separates, which is filtered off, washed with water and recrystallized from about 50 parts of water containing a small amount of sodium hydroxide. The air-dried product thus obtained is the monohydrate of l-allyl-3-methyl- 6 amino 1,2,3,4 tetrahydro 2,4 pyrimidinedione, melting with partial dehydration at about '74-75 C. The anhydrous 1-allyl-3-methyl-6- amino l,2,3,4 tetrahydro 2,4 pyrimidinedione is obtained by heating the hydrate at C. for 48 hours and recrystallizing from ethyl acetate. The crystals melt at about 143-144" C. This same product can also be obtained by methylating 1-allyl-6-amino-1,2,3,4-tetrahydro- 2,4-pyrimidinedione with methyl iodide according to the procedure of Example 6. The structural formula of this product is HQN-C (3:0

H /NC H:

Example 3 334 parts of 1-allyl-6-amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione are dissolved in a solution of 88 parts of sodium hydroxide in 1100 parts of water. While this mixture is stirred rapidly at 50 C., 430 parts of diethyl sulfate are added in the course of 30 minutes. Stirring is continued at 50-55 C. for one hour longer, and an alkaline reaction is maintained by occasional additions of small portions of 20% aqueous sodium hydroxide solution, about 300 parts in all being required. On cooling, the l-allyl-3-ethyl- 6 amino l,2,3,4 tetrahydro 2,4 pyrimidinedione separates as the monohydrate; it is filtered oil, washed with cold water, and recrystallized from water containing a small amount of sodium hydroxide to hold in solution any unreacted l allyl 6 amino 1,2,3,4 tetrahydro 2,4-pyrimidinedione. The air dried product thus obtained contains 1 mole of crystal water and melts over a wide range with dehydration at 75-115 C. After dehydration by treatment with anhydrous ether, the anhydrous l-allyl-3-ethyl- 6 amino 1,2,3,4 tetrahydro 2,4 pyrimidinedione melts sharply at about l43-l44 C.

Example 4 300 parts of the ethyl ester of cyanoacetic acid and parts of allylarnine are mixed and maintained for one hour at 55 C. The mixture is then cooled and the precipitate is filtered, washed with petroleum ether and then with diethyl ether. The resulting N-allyl-cyanoacetamide, recrystallized from toluene, melts at about 6366 C. A mixture of 240 parts of this amide and 270 parts of ethylisocyanate in 1700 parts of toluene is heated to refluxing temperature for 24 hours'with stirring. After cooling and standing, the solution is seeded with N- allylcyanoacetamide and the unreacted material precipitates. The filtrate is evaporated at 60 C. in vacuo to a syrup. To the N-allyl-N- cyanoacetyl-N-ethylurea a sufficient amount of 10% sodium hydroxide is added to raise the pH to 10. Cyclization occurs with great violence. After cooling the l-ethyl-3-allyl-6amino-1,2,3,4- tetrahydro 2,4 pyrimidinedione is filtered, washed with ice water and recrystallized from water, using charcoal as a decolorizing agent.

Aft-er dehydration this compound melts at about 142-144 C. although some sintering is observed at 132-l34 C.

Example 300 parts of l l-ethyl-I\ '-allylurea are dissolved in 650 parts of acetic anhydride and 630 parts of glacial acetic acid. Then 190 parts of cyanoacetic acid are added and the mixture is maintained at 65 C. for 2 hours. Most of the solvent is then distilled 005 at 20 mm. pressure and 60 C. 100 parts of water are added to the syrup and the distillation is resumed. The remaining syrup consists principally of N-cyanoacetyl-N- ethyl-N-allylurea but also contains a significant amount of N-cyanoacetyl-N-allyl-N-ethylurea. 50 parts of this syrup are dissolved in 50 parts of sodium hydroxide and the pH is adjusted to 10 by addition of 70% sodium hydroxide. The mixture is maintained at 60 C. for 5 minutes. On cooling crystals separate which are collected on a filter. These crystals consist principally of the l-al1yl-3-ethyl-6-amino-1,2,3A-tetrahydro- 2,4-pyrimidinedione but contain a significant amount of 1-ethyl-3-allyl-6-amino-1,2,23,4-tetrahydro 2,4 pyrimidinedione. These crystals, which contain about 80% l-allyl-3-ethyl-6- amino 12,3,4 tetrahydro 2,4 pyrimidinedione and 20% 1-ethyl-3-allyl-6-amino-l2,3,4- tetra-hydro-2,4 pyrimidinedione, melt after dehydration at about l32-133 C. The ethyl allyl xanthine derivative prepared therefrom melts at about 182-185 C.

Example 6 100 parts of l-a1lyl-6-amino-1,2,3,4-tetrahydro-2A-pyrimidinedione are dissolved in a solution of 26.4 parts of sodium hydroxide in 200 parts of water. After addition of 790 parts of ethanol and 113 parts of n-propyl iodide the mixture is heated at refluxing temperature for two hours. The alcohol is then removed by evaporation on the steam bath, and the syrupy residue is taken up in 1000 parts of hot water, treated with charcoal, and filtered. On cooling a crystalline material separates from the filtrate. This is cooled and recrystallized from about 250 parts of hot water. The "air-dried product that is obtained is the monohydrate of 1-allyl-3-npropyl 6 amino 1,2,3,4 tetrahydro 2,4- pyrimidinedione, which melts with partial dehydration at about 88-92" C. On treatment with anhydrous ether, the anhydrous l-allyl-S-npropyl 6 amino l,2,3,4= tetra-hydro 2,4- pyrimidinedione is obtained which melts at about 117-118 C.

Example 7 50 parts of l-allyl-6-amino-1,2,3,4-tetrahydro- 2,4-pyrimidinedione are dissolved with warming in a solution of 13.2 parts of sodium hydroxide in 100 parts of water. After addition of 400 parts of ethanol and 61 parts of n-butyl iodide, the mixture is heated on the steam bath under a reflux condenser for two hours. The solution is treated briefly with decolorizing carbon, filtered, and the alcohol evaporated on the steam bath. The syrup thus obtained is covered with 500 parts of water containing about 10 parts of sodium hydroxide (to dissolve any unchanged 1- allyl 0 amino 12.3.4 tetrahydro 2,4- pyrimidincdione). On standing, the syrup slowly crystallizes. The crystals are filteredoff, washed with water, and recrystallized from 30% aqueous ethanol. The monohydrate of -1-allyl-3-n-butyl- 6 -amino 123,4 tetra-hydro -2-,4 pyrimidinedione separates out, and after air-drying, melts somewhat unsharply at 80-85 C.

The anhydrous compound obtained by heating the monohydrate for 24 hours at 80 C. and recrystallizing from ethyl acetate melts at about -97 C.

Example 8 185 parts of isobutylamine are dissolved in 900 parts of benzene and cooled in an ice bath while 200 parts of allyl isocyanate are added gradually. The temperature should not be permitted to rise above 30 C. The benzene is removed by vacuum distillation and the N-allyl-N-isobutylurea crystallizes spontaneously. 38 parts of this urea derivative are dissolved in parts of acetic anhydride. To this solution 27 parts of cyanoacetic acid are added and the temperature is maintained at 55-60" C. for 2 hours. The solvent is removed as completely as practicable by vacuum distillation at 20 mm. pressure and 60 C., after which 75 parts of water are added and the solution is redistilled under the same conditions until a syrup remains which contains a mixture of N-cyanoacctyl-N-isobutyl-N'-allylurea and N- cyanoacetyl-N-allyl-N-isobutylurea. This syrup is dissolved in an equal volume of a 10% sodium hydroxide solution, and the pH is adjusted to 10 by addition of 70% sodium hydroxide. The mixture is maintained at 70 C. for 5 minutes and upon cooling crystals separate. These crystals are recrystallized twice from 40-45% ethanol. The resulting white crystalline product consists of the hydrate of 1-allyl-3-isobutyl-l,2,3,4-tetrahydro-2,e-pyrimidinedione and of 1-isobutyl-3- allyl 1,2,3,e tetrahydro 2,4 pyrimidinedione. The dehydrated mixture melts at about 9297 C.

Example 9 30 parts of n-hexylamine in '70 parts of benzene are maintained at about 20 C. while 25 parts of allyl isocyanate are slowly added. The product is evaporated in vacuo and the N-hexyllW-allylurea crystallizes in long needles. The urea derivative thus obtained is reacted with 30 parts of cyahoacetic acid and 100 parts of acetic anhydride for two hours at 60 C. The solvent is removed by vacuum distillation at 20 mm. and 60 C. as far as practical. The syrup is diluted with water and vacuum distillation resumed. This process is repeated and the final syrup consisting of N-allyl-N-cyanoacetyl-N-hexylurea, containing also a small but significant amount of N-hexyl-Ncyanoacetyl-N-allylurea, is treated with 10% sodium hydroxide so as to raise the pH above 10 at a temperature of about 70 C. The mixture consisting primarily of l-hexyl-B- allyl 6 amino 1,2,3,4 tetrahydro 2,4- pyrimidinedione and a smaller amount of l-allyl- 3 hexyl 0 amino 12,3,4 tetrahydro 2,4- pyrimidinedione does not crystallize spontaneously. The 5-nitroso derivative thereof is pre pared by nitrosating in alcohol with sodium nitrite and acetic acid. The nitroso derivative, re crystallized from 50% alcohol, melts at about let- C.

Example 10 20 parts of phenyl isocyanate are added dropwise to a solution of 10 parts of allylamine in 50 parts of benzene, the reaction mixture being stirred and maintained at a temperature below 25 C. Evaporation in vacuo yields the N-allyl- N'-phenylurea. The compound thus obtained is treated with 19 parts of cyanoacetic acid and 60 parts of acetic anhydride for two hours at 60 C.

7 Vacuum distillation at 20 mm. and 60 C. and crystallization yields a mixture of N-allyl-N- cyanoacetyl-N'-phenylurea and N-phenyl-N- cyanoacetyl-N'-allylurea. This mixture, recrystallized from alcohol, melts at about 114-115 C. These crystals are treated with 10% sodium hydroxide solution to raise the pH to 10. After heating at 75 C. for minutes, the mixture is cooled and the precipitate collected on a filter. Two successive recrystallizations from 50% alcohol yield white crystals melting at about 190-194 C. These crystals consist primarily of l-phenyl- 3 allyl-fi-amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione but contain an admixture of l-allyl-3- phenyl-S-amino 1,2,3,4 tetrahydro-2,4-pyrimidinedione.

Example 11 To a solution of 30 parts of benzylamine in 70 parts of benzene maintained at a temperature below 25 C., 25 parts of allyl isocyanate are slowly added with stirring. The solvent is removed under vacuum. To the Dl-allyl-hV-benzylurea thus obtained, 30 parts of cyanoacetic acid and 100 parts of acetic anhydride are added. Vacuum distillation results in the formation of a syrup. After addition of 50 parts of water, vacuum distillation is resumed and this process is repeated once more. The syrup thus obtained contains a mixture of N-allyl-N-cyanoacetyl-N-benzylurea and N-benzyl-N-cyanoacetyl-N-allylurea. The pH is raised to by addition of a 10% solution of sodium hydroxide. If necessary, the tempera ture is raised by heating to 70 C. After 5 minutes the solution is cooled and the gummy precipitate is filtered. On treatment with 50% ethanol the precipitate crystallizes and upon crystallization from 75% alcohol, white crystals are obtained which melt at about 218-220 C. They consist primarily of 1-benzyl-3-allyl-6-amino-1,23,4- tetrahydro-2,4-pyrimidinedione, but contain an admixture of l-allyl-Z-benzyl-B-amino-1,23,4- tetrahydro-2,4-pyrimidinedione.

Example 12 To a chilled solution of 184 parts of crotylisocyanate in 700 parts of benzene, 122 parts of eaminoethanol are added gradually with stirring, the temperature being maintained below 25 C. The solvent is removed under vacuum. 240 parts of the N-(fl-hydroxyethyl) -N-crotylurea thus obtained are reacted with 210 parts of cyanoacetic acid and 700 parts of acetic anhydride for 2 hours at 60 C. The solvent is evaporated in vacuo at 60 C. as far as practical. The residual syrup is diluted with an equal volume of water and vacuum distillation resumed. After repetition of this dilution and evaporation process, the syrupy mixture of N- (B-hydroxyethyl) -N-cyanoacetyl-N- crotylurea and N-crotyl-N-cyanoacetyl-N-( hydroxyethyhurea is treated with a sumcient amount of 10% potassium hydroxide to raise the pH to 10. The alkali is added p-ortionwise to prevent a rise in temperature above 70 C. Cyclization at 60-70 C. is completed within a few minutes. Upon concentration and chilling, there precipitates a mixture of the isomers, in which the 1-crotyl-3- (c-hydroxyethyl) -6-amino-1,2,3,4- tetrahydro 2,4 pyrimidinedione predominates greatly over the l-(fi-hydroxyethyl)-3-crotyl-6- amino-1,2,3,4-tetrahydro-2,4-pyrimidinedione.

Example 13 194 parts of methallylurea are dissolved in 260 parts of acetic anhydride and treated with 1'70 parts of cyanoacetic acid. After heating and stirring at 70-75 C. for one half hour or until crystallization occurs, 800 parts of hot water are added. Upon cooling precipitation occurs. The N-cyanoacetyl-N'-methallylurea thus obtained melts at about 143-145 C. after another recrystallization from water. Cyclization is effected by dissolving in 400 parts of 5% sodium hydroxide solution and treatin with a suflicient amount of 70% sodium hydroxide to raise the pH to about 10. After heating for one half hour at C. the pH is lowered by addition of dilute hydrochloric acid to about 4, and the l-methallyl-G-amino- 1,2,3,4-tetrahydro-2,4 pyrimidinedione collected on a filter and recrystallized from dilute ethanol, using charcoal as a clarifying agent. The resulting pure crystals melt at about 266-268 C.

Example 14 To a solution of 50 parts of l-methallyl-fiamino-1,2,3,4-tetrahydro-2,4-pyrimidinedione in 150 parts of a 12% sodium hydroxide solution, 50 parts of dimethyl sulfate are added dropwise at 55 C. After completion of this reaction the solution is neutralized by addition of concentrated sodium hydroxide and cooled. The 1 methallyl 3 methyl 6 amino 1,2,3,4 tetrahydro-2,4-pyrimidinedione is collected on a filter and recrystallized from a concentrated aqueous solution. The compound, which melts at about 145-146 C., has the following structural formula ll (Jr-CH3 Example 15 To a cooled and stirred solution of 142 parts of methallylamine in 900 parts of benzene, 156 parts of ethyl isocyanate are added dropwise. Upon concentration in vacuum N-ethyl-N-methallylurea is obtained.

260 parts of this urea derivative are dissolved in 500 parts of acetic anhydride and treated with 157 parts of cyanoacetic acid at 60 C. and heated at that temperature for 2 hours. The solution is then concentrated in vacuum to a syrup. parts of water are added and the vacuum distillation is repeated and the remaining syrup contains a mixture of N-cyanoacetyl-N-ethyl-N- methallylurea, and a small quantity of N-cyanoacetyl-N-methallyl-N-ethylurea.

This syrup is treated with sufficient 20% sodium hydroxide solution to raise the pH to 10. A violent reaction occurs. The reaction mixture is diluted with 50 parts of water, stirred, cooled and filtered. The material collected on the filter is recrystallized from 10% ethanol to yield a mixture of l-methallyl-3-ethyl-6-amino-1,2,13,4- tetrahydro-2,4-pyrimidinedione and 1-ethyl-3- methallyl 6 amino 1,2,3,4 tetrahydro 2,4 pyrimidinedione melting at about 157-159" C.

Example 16 To a solution of 35 parts of p-chloroethyl isocyanate in 50 parts of benzene, a solution of 20 parts of n-propylamine in 50 parts of benzene is added dropwise with ice cooling and stirring until a sample no longer shows acidic reaction.

Stirring is continued for 30 minutes after which the reaction product is collected on a filter and washed once with benzene. The N-(c-chloroethyl) -N-propylur.ea is extracted by hot benzene.

50 parts of this urea derivative are dissolved in 200 parts of acetic anhydride and heated with 31 parts of cyanoacetic acid at 55 C. for 2 hours with stirring. The reaction mixture is then concentrated at about 55 C. and 16 mm. pressure, treated with 200 parts of hot water and concentrated further to a thick syrup. More water is added and after reconcentration the syrup is treated with a sufiicient amount of 15% sodium hydroxide solution to raise the pH to about 10 at a temperature of about 70 C. The resulting soft precipitate is separated by decantation of the supernatant and the precipitate is granulated by treatment with ethyl acetate. Recrystallized from water, the mixture of 1-propyl-3- vinyl 6 amino 1,2,3,4 tetrahydro 2,4 pyrimidinedione and l-vinyl-3-propyl-6-amino- 1,2,. A-tetrahydro-2A-pyrimidinedione melts at about 1204-207 C. On treatment with nitrous acid it forms the reddish purple mixture of the 1 propyl 3 vinyl 5 nitroso 6 amino 1,2,3,4 tetrahydro 2,4 pyrimidinedione and 1 vinyl 3 propyl 5 nitroso 6 amino l,2,3,4-tetrahydro-2,4-pyrimidinedione.

Example 17 40 parts of N-propargyl-N-ethylurea are dissolved in 110 parts of acetic anhydride and then heated with 32 parts of cyanoacetic acid for 2 hours at 55 0. Most of the solvent is then distilled off at mm. pressure, 50 parts of water are added and vacuum concentration is resumed. The resulting light yellow syrup is taken up in ether and first shaken with ice cold, dilute sodium bicarbonate to neutrality and then with water. Evaporation yields a. mixture of N-cyanoacetyl-N-ethyl-N'-propargylurea and N-cyanoacetyl-N-propargyl-N-ethylurea. This syrup is treated with a sufiicient amount of a 10% aqueous sodium hydroxide solution to maintain the pH at 10 while the solution is kept at 85 C. for 5 minutes with stirring. After neutralization with dilute hydrochloric acid and concentration in vacuum, the residue is taken up in alcohol. This solution is evaporated to dryness and the residue taken up in absolute alcohol, stirred with charcoal, freed of the remaining sodium chloride and the charcoal by filtration and evaporated to yield the very slightly yellowish mixture of 1 propargyl 3 ethyl 6 amino 1.2.3.4 tetrahydro-2,4-pyrimidinedione and 1-ethyl-3- propargyl 6 amino 123,4 tetrahydro 2,4 pyrimidinedione. Treatment of an aqueous solution of this mixture with sodium nitrite and acidification with acetic acid yields a rubycolored 5-nitroso derivative.

Example 18 A solution of 1'? parts of N-propargyl-N- phenylurea in 35 parts of acetic anhydride is heated with stirring at 60 C. for 2 hours with 10 parts of cyanoacetic acid. Vacuum distillation at 16 mm. pressure and 55 C. to a syrup, addition of 50 parts of water and further concentration yields a dark orange, syrupy mixture of the N-cyanoacetyl-N-propargyl-N-phenylurea and N-cyanoacetyl N phenyl N propargylurea. This mixture is treated with a suificient amount of 10% sodium hydroxide to raise the pH to 10. The alkali is added slowly and the temperature l HO N-R wherein one of the radicals R represents a lower, unsaturated, aliphatic hydrocarbon radical and the other radical R. represents a member of the class consisting of lower alkyl, lower hydroxyalkyl, benzyl, and phenyl radicals.

2. A fi-amino-1,2,3.4-tetrahydro 2,4 pyrimidinedione derivative of the structural formula wherein one of the radicals R represents a lower unsaturated, aliphatic hydrocarbon radical and the other radical R represents a lower alkyl radical.

3. An alkenylalkyl-G-amino-l,2,3,4-tetrahydro- 2,4-pyrimidinedione of the structural formula l HO N-R wherein one of the radicals R represents a, lower alkenyl radical and the other radical R represents a lower alkyl radical.

4. An alkylalkyl- 6 -amino-1,2,3,4-tetrahydro- 2,4-pyrimidinedione of the structural formula HO I l-R wherein one of the radicals R represents an allyl radical and the other radical R represents a lower alkyl radical.

5. A l allyl-3-(lower) all yl-6-amino-1,2,3,4- tetrahydro-2,4=-pyrimidinedione.

6. A 1 (lower)-alkyl-3-allyl-6-amino-1,2,3,4- tetrahydro2,4-pyrimidinedione.

11 '7. A methallylalkyl 6 amino-1,2,3,4-tetrahydro-2A-pyrimidinedi0ne of the structural formula wherein one of the radicals R represents a methallyl radical and the other radical R represents a lower alkyl radical.

8. A l metha1lyl-3-(lower)-alky1 6 amino- 1,2,3,4:-tetrahydr0-2,4-pyrimidinedione.

9. An alkenylalkyl-6-amino-1,2,3,4-tetrahydr0- 2,4-pyrimidinedione of the structural formula wherein one of the radicals R represents a lower alkenyl radical and the other radical R repre- 30 sents a lower alkyl radical.

10. A proparglyalkyl-G-amino-1,2,3,l-tetrahy- 12 dro-2,4-pyrimidinedione or the structural formula 10 wherein one of the radicals R represents a propargyl radical and the other radical R represents a lower alkyl radical.

11. A propargylethyl-G-amino-l,2,3,4tetrahydro-2,4-pyrimidinedione of the structural formula No references cited. 

1. A 6-AMINO-1,2,3,4-TETRAHYDRO - 2,4 - PYRIMIDINEDIONE DERIVATIVE OF THE STRUCTURAL FORMULA 